The present invention relates to a process for making desvenlafaxine. Desvenlafaxine, chemically 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of the formula (1):
is an active metabolite of the known pharmaceutical agent venlafaxine, the compound of formula (2).
As is seen from the above, desvenlafaxine differs from venlafaxine in that the former is missing a methyl group in the phenolic substituent; e.g. is “des-methyl” hence ‘desvenlafaxine.’ The molecule of the formula (1) has one center of optical activity. The desvenlafaxine as used herein comprises the racemic form, the single enantiomer, and mixtures of enantiomers. Desvenlafaxine is being tested as an improved form of venlafaxine and may one day replace venlafaxine in medical treatments. Accordingly, several patents are already known concerning desvenlafaxine.
For example, desvenlafaxine was disclosed in the patent EP 112669/U.S. Pat. No. 4,535,186 owned by American Home Products. Furthermore, it has been disclosed in the patent application WO 00/59851 of Sepracor. More recently, WO 02/64543 discloses that an advantageous salt form of desvenlafaxine is a (1:1) succinate salt and that the crystalline product is a monohydrate.
Various processes are also known for making desvenlafaxine. Many of these processes start from venlafaxine and convert it to desvenlafaxine via, in essence, a demethylation of venlafaxine. Such a process has been generically suggested in U.S. Pat. No. 5,043,466.
However, in general, the substituted phenoxy group is a very stable moiety against nucleophilic substitution and thus the demethylation reaction requires special reagents and drastic conditions. Furthermore, the reagent should not attack the tertiary hydroxy group in the molecule.
WO 00/59851, WO 00/32556 and WO 00/32555 disclose a process for producing desvenlafaxine starting from venlafaxine using lithium diphenylphosphide (made in situ from diphenyl phosphine and n-butyllithium) as the demethylation agent and tetrahydrofuran (THF) as a solvent. A disadvantage of this process is that the concentration of the material in the solvent is very low. Apparently the demethylation of venlafaxine is complicated by the formation of a largely insoluble lithium salt of venlafaxine that is formed in the THF solvent.
WO 02/64543 discloses that an alkali metal salt of a trialkyl borohydride (e.g. L-selectride) at a temperature from 60 to 140° C. may be used for demethylation. The formed alkali metal salt of the desvenlafaxine is converted to the free base of desvenlafaxine by a neutralization with an acid. The process is relatively expensive due to the cost of the reagents.
WO 03/48104 discloses a process of demethylation employing a dodecane thiol (or benzenethiol) in the presence of sodium methanolate in methanol as the demethylation agent, polyethyleneglycol 400 as the solvent, reaction temperature of 180-200° C. and a reaction time of 2-5 hours. After neutralization of the reaction product to pH approx. 9.5 in the presence of isopropanol, the free base of desvenlafaxine is obtained. Polyethylene glycol can be disadvantageous as it is difficult to be recycled after use and the overall process suffers from the need for high reaction temperatures.
Therefore, it would be desirable to find an alternative and preferably economically efficient process for demethylation of venlafaxine.